Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019.

The aim of this study was to investigate the correlations between serum calcium and clinical outcomes in patients with coronavirus disease 2019 (COVID-19). In this retrospective study, serum calcium levels, hormone levels and clinical laboratory parameters on admission were recorded. The clinical outcome variables were also recorded. From February 10 to February 28, 2020, 241 patients were enrolled. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, and median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positively correlated with VD levels (P =0.004) but negatively correlated with PTH levels (P =0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidences of organ injury and septic shock, and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P <0.001), 0.905 (P =0.001), and 0.929 (P <0.001), respectively. In conclusion, serum calcium was associated with the clinical severity and prognosis of patients with COVID-19. Hypocalcemia may be associated with imbalanced VD and PTH levels.

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

An association of type 1 diabetes mellitus with auditory dysfunction: A systematic review and meta-analysis.

OBJECTIVE: To establish the relationship between the presence of type 1 diabetes mellitus (DM) and auditory dysfunction in clinical settings by a systematic review and meta-analysis of currently available published data. DATA SOURCES AND REVIEW METHODS: The electronic databases PubMed, Embase, and Wanfang Data were searched for eligible relevant studies up to May 2016, and the reference lists of the retrieved articles were used for additional manual search. All the articles included in this pooled analysis were determined according to the preset inclusion and exclusion criteria. Meta-analysis of pooled data was performed using Review Manager 5.3. RESULTS: A total of 15 studies were included for further combined analysis. The results showed that patients with type 1 diabetes had a significantly higher prevalence of hearing loss than controls (odds ratio = 49.08, 95% confidence interval = 12.03-200.31, P < 0.00001); standardized mean of differences (SMD) of pure tone audiometry at 4,000 Hz between diabetes and controls was 0.87 (Z = 2.22, P = 0.03, I2 = 95%); SMD of the latency time was 0.54 (Z = 2.69, P = 0.007, I2 = 78%) for waves III and 0.61 (Z = 2.38, P = 0.02, I2 = 86%) for wave V, respectively; and SMD of the interpeak latency time was 0.41 (Z = 2.84, P = 0.005, I2 = 39%) for waves I to III and 0.61 (Z = 2.67, P = 0.008, I2 = 81%) for waves I to V, respectively, between diabetics and controls. CONCLUSION: Our study reveals that there is relationship between the presence of type 1 DM and an increased risk for developing mild and subclinical hearing impairment. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1689-1697, 2017.

Use of taxane-containing induction chemotherapy in combination with concurrent chemoradiotherapy in Chinese patients with locally advanced nasopharyngeal carcinoma: a meta-analysis.

PURPOSE: Taxane-containing induction chemotherapy (IC) regimens in combination with concurrent chemoradiotherapy (CCRT) have been compared with non-taxane-containing IC combined with CCRT in randomized controlled trials (RCTs) in Chinese patients with advanced nasopharyngeal carcinoma (NPC). This meta-analysis aimed to systematically evaluate their clinical efficacy and safety profiling in this ethnic population. METHODS: The electronic databases, PubMed, Embase, MEDLINE, and Chinese Biomedical Database, were searched for eligible studies. The outcomes included overall response rate (ORR), 1-year survival rate, and different types of adverse events. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: A total of 12 RCTs (representing 835 patients) were identified. The pooled analysis showed that taxane-containing regimens had a significant improvement in ORR for nasopharyngeal lesion (OR =4.57, 95% CI =1.14-18.30, P=0.032, z=2.15) but not in cervical lymph nodes (OR =1.23, 95% CI =0.65-2.36, P=0.532, z=0.64) and in 1-year survival rates (OR =1.19, 95% CI =0.10-14.82, P=0.893, z=0.13) compared with non-taxane-containing regimens. Regarding the adverse events and toxicities, grade 3-4 leukopenia and neutropenia were significantly different between the two groups (P<0.001) in favor of the non-taxane-containing regimens, but grade 3-4 vomiting was significantly different between the two groups (P<0.005) in favor of the taxane-containing regimens. CONCLUSION: When combined with CCRT, taxane-containing IC regimens may be more efficient for short-term local control in Chinese patients with locally advanced NPC than the non-taxane-containing IC regimens. Moreover, the major toxic effects, which were bone marrow suppression, could be tolerated by majority of patients. More long-term follow-up and high-quality trials of NPC are needed to validate our findings.

Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up-regulation of Vegfr3 gene expression in lymphatic endothelial cells.

Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.

Death receptor 3 mediates TNFSF15- and TNFα-induced endothelial cell apoptosis.

Tumor necrosis factor superfamily 15 (TNFSF15) suppresses angiogenesis by specifically inducing apoptosis in proliferating endothelial cells. Death receptor 3 (DR3), a member of the TNF receptor superfamily (TNFRSF25), has been identified as a receptor for TNFSF15 to activate T cells. It is unclear, however, whether DR3 mediates TNFSF15 activity on endothelial cells. Here we show that siRNA-mediated knockdown of DR3 in an in vivo Matrigel angiogenesis assay, or in adult bovine aortic endothelial (ABAE) cell cultures, leads to resistance of endothelial cells to TNFSF15-induced apoptosis. Interestingly, DR3-depleted cells also exhibited markedly diminished responsiveness to TNFα cytotoxicity, even though DR3 is not a receptor for TNFα. Treatment of the cells with either TNFSF15 siRNA or a TNFSF15-neutralizing antibody, 4-3H, also results in a significant inhibition of TNFα-induced apoptosis. Mechanistically, DR3 siRNA treatment gives rise to an increase of ERK1/2 MAPK activity, and up-regulation of the anti-apoptotic proteins c-FLIP and Bcl-2, thus strengthening apoptosis-resisting potential in the cells. These findings indicate that DR3 mediates TNFSF15-induced endothelial cell apoptosis, and that up-regulation of TNFSF15 expression stimulated by TNFα is partly but significantly responsible for TNFα-induced apoptosis in endothelial cells.

TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1.

Mouse bone marrow-derived Lin(-)-Sca-1(+) endothelial progenitor cell (EPC) has pluripotent abilities such as supporting neovascularization. Vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) (Flt1) recognizes various VEGF isoforms and is critically implicated in a wide range of physiological and pathological settings, including vasculogenesis. Mouse EPC expresses two isoforms of VEGFR1: mFlt1, which transmits ligand-induced signals; and sFlt1, which acts as a negative regulator by sequestering ligands of VEGF receptors. How the relative levels of mFlt1 and sFlt1 are regulated is not yet clear. We report here that tumor necrosis factor superfamily 15 (TNFSF15) (also known as VEGI or TL1A), an endothelial cell-secreted cytokine, simultaneously promotes mFlt1 degradation and up-regulates sFlt1 expression in EPC, giving rise to disruption of VEGF- or PlGF-induced activation of eNOS and MAPK p38 and effective inhibition of VEGF-driven, EPC-supported vasculogenesis in a murine Matrigel implant model. TNFSF15 treatment of EPC cultures facilitates Akt deactivation-dependent, ubiquitin-assisted degradation of mFlt1 and stimulates sFlt1 expression by activating the PKC, Src, and Erk1/2 signaling pathway. Additionally, TNFSF15 promotes alternative splicing of the Flt1 gene in favor of sFlt1 production by down-regulating nuclear protein Jumonji domain-containing protein 6 (Jmjd6), thus alleviating Jmjd6-inhibited sFlt1 expression. These findings indicate that TNFSF15 is a key component of a molecular mechanism that negatively modulates EPC-supported vasculogenesis through regulation of the relative levels of mFlt1 and sFlt1 in EPC.

[Treatment of endonasal-encephalomeningocele by transnasal endoscopic surgery].

OBJECTIVE: To inquire into the feasibility of transnasal endoscopic surgery for endonasal encephalomeningocele, and to put forward the basic management guidelines. METHOD: Five cases of endonasal encephalomeningocele were managed by transnasal endoscopic surgery. Different surgical techniques were applied according to the size and shape of skull base defect. At the same time, one-stage repair of skull base defect was achieved by applying muscle, fascia, cartilage and bone. RESULTS: All 5 patients were successfully treated without complication and relapse during 1-5 year follow-up. CONCLUSION: Endonasal type encephalomeningocele can be managed by transnasal endoscopic surgery. If the skull base defect is less than 0.5 cm, it can be repaired by packing muscle and fascia. If the defect is larger than 0.5 cm, the cartilage or bone should be used to repair the skull base.